Currently, the commercial vaccine preparations are mostly available in the injection form. The injection form vaccine induces the immune response (IgG antibody production) in blood (systemic) but does not induce the mucosal immune response (IgA antibody production), and thus prevents the post-infection pathogen growth but has a problem in the protection against the pathogen infection by mucosal route.
Under the circumstances, the vaccination via mucosal route has been drawing attention in recent years. In particular, the development of a vaccine containing an influenza virus as an antigen for mucosal administration (transnasal administration) has been in a high profile.
The mucosal administration vaccine induces the systemic immunity (IgG antibody production) and also induces the mucosal immunity (IgA antibody production). The IgA antibody does not strictly discriminate the pathogen type of a disease to be targeted, is adaptable to ever-changing pathogen epidemic every year and is thus considered to be effective for the pandemic prevention.
One of the reasons for the transnasal administration vaccine to attract attention is that the antigen administration to the gastrointestinal mucosa is susceptible to the influences of gastric juice and proteases which are hardly evitable, whereas the antigen administration to the transnasal mucosa is free of these influences. Additionally, there is an antigen-recognition tissue called NALT on the nasal cavity mucosa which is beneficial for immune response. This is another reason for the transnasal administration vaccine to gain interests.
However, the antigen administration to the nasal cavity mucosa, while being highly effective, have had drawbacks in that it is most likely to cause critical adverse effects such as acute encephalopathy, or the like; the transnasal administration per se is cumbersome and difficult to practice on the elderly, infant, or the like; and the stable effect is not assured due to physical factors such as nasal mucus, or the like.
On the other hand, there have also been many attempts to induce the systemic immunity and mucosal immunity via oral administration of an antigen through the gastrointestinal mucosa (intestines), and the like, after swallowing. The concern here is how the antigen breakdown caused by the gastric juice or proteases is prevented. To solve the problem, techniques have been developed to neutralize the gastric juice by a large content of an antacid, or to protect an antigen using coating techniques such as microspheres, or the like.
However, the development was practically successful only on vaccines intrinsically highly stable in the gastric juice such as live attenuated poliovirus vaccine and live attenuated rotavirus vaccine.
Alternatively, an allergy vaccine is an example of the oral administration preparation to induce an immune response via the oral cavity mucosa (particularly sublingual mucosa) delivery without swallowing. This vaccine is termed as sublingual immunotherapy (SLIT) and works by continuously administering sublingually a plant-derived extract containing a protein to be an allergy antigen (allergen) to boost the immunotolerance against the allergen and reduce the allergy reaction. In recent years, SLIT is now widely accepted in Europe and many products are available in the market today.
The therapy using such a preparation which induces the immune response via the oral cavity mucosa route, particularly the sublingual mucosa route, is the focus of attention because it provides better patient's QOL and has a lower risk of anaphylactic shock, critical adverse effect, than the conventional therapy which required the subcutaneous injection of an allergen (subcutaneous immunotherapy).
However, SLIT has been to use preparations only for boosting a specific immunotolerance, but has been not a therapy to activate the immunity. The oral cavity mucosa is generally not likely to develop immunity, and the activation of immunity, even if the immunotolerance is developed, has been considered to be difficult.
Examples of the induction of the mucosal immunity and systemic immunity via the oral cavity mucosa route, particularly the sublingual mucosa route, are reported including the following.
OVA-specific systemic immune response (IgG production) and OVA-specific mucosal immune response (IgA production) are proposed to have been confirmed when OVA used as an antigen and cholera toxin used as an adjuvant were administered sublingually (see, for example, Patent Literature 1). However, in the proposal, highly neurotoxic cholera toxin was used as the adjuvant and the safety issue was left to be cleared.
Using OVA as an antigen and 3 de-O-acylated monophosphoryl lipid A, a TLR4 agonist, as an adjuvant and administering them sublingually have been proposed to bring about OVA-specific systemic immune response (IgG production) and OVA-specific mucosal immune response (IgA production) as well (see, for example, Patent Literature 2). In this proposal, a TLR4 agonist was sublingually administered as an adjuvant, however, no example regarding an antigen derived from an infectious disease was presented and the versatility of the effect to the antigen type was not evident. Additionally, the comparatively large doses of OVA being 80 to 160 μg and 3 de-O-acylated monophosphoryl lipid A being 20 to 40 μg are not practical when considering the safety.
A proposal on a method for synthesizing glucopyranosyl lipid, a synthetic adjuvant, (see, for example, Patent Literature 3) also describes the mucosal immune response induction by the mucosal administration of an antigen in combination with the adjuvant. The inductions of serum IgG and IgA in a nasal wash are also proposed by the administration of MALP-2, a TLR2/6 ligand, together with β-galactosidase used as an antigen to the nasal cavity of a mouse (see, for example, Patent Literature 4). However, no example regarding an antigen derived from an infectious disease or administration thereof to the oral cavity mucosa was presented, and thus the versatility of the effect was not evident. Using c-di-GMP or c-di-AMP, cyclic dinucleotide, as an adjuvant together with β-galactosidase as an antigen and intranasally administering them to a mouse have been also proposed to bring about the induction of serum IgG (see, for example, Patent Literature 5), however, the proposal does not mention the IgA induction via transnasal administration and no example regarding an antigen derived from an infectious disease or administration thereof to the oral cavity mucosa was presented, and thus the versatility of the effect was not evident.